Vitamin B5 metabolism is essential for vacuolar and mitochondrial functions and drug detoxification in fungi.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
23 Jul 2024
23 Jul 2024
Historique:
received:
10
11
2023
accepted:
17
07
2024
medline:
24
7
2024
pubmed:
24
7
2024
entrez:
23
7
2024
Statut:
epublish
Résumé
Fungal infections, a leading cause of mortality among eukaryotic pathogens, pose a growing global health threat due to the rise of drug-resistant strains. New therapeutic strategies are urgently needed to combat this challenge. The PCA pathway for biosynthesis of Co-enzyme A (CoA) and Acetyl-CoA (AcCoA) from vitamin B5 (pantothenic acid) has been validated as an excellent target for the development of new antimicrobials against fungi and protozoa. The pathway regulates key cellular processes including metabolism of fatty acids, amino acids, sterols, and heme. In this study, we provide genetic evidence that disruption of the PCA pathway in Saccharomyces cerevisiae results in a significant alteration in the susceptibility of fungi to a wide range of xenobiotics, including clinically approved antifungal drugs through alteration of vacuolar morphology and drug detoxification. The drug potentiation mediated by genetic regulation of genes in the PCA pathway could be recapitulated using the pantazine analog PZ-2891 as well as the celecoxib derivative, AR-12 through inhibition of fungal AcCoA synthase activity. Collectively, the data validate the PCA pathway as a suitable target for enhancing the efficacy and safety of current antifungal therapies.
Identifiants
pubmed: 39043829
doi: 10.1038/s42003-024-06595-7
pii: 10.1038/s42003-024-06595-7
doi:
Substances chimiques
Antifungal Agents
0
Pantothenic Acid
19F5HK2737
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
894Subventions
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
ID : AI123321, AI138139, AI152220, and AI136118
Informations de copyright
© 2024. The Author(s).
Références
Lyman, M. et al. Worsening Spread of Candida auris in the United States, 2019 to 2021. Ann. Intern. Med. https://doi.org/10.7326/M22-3469 (2023).
Bosetti, D. & Neofytos, D. Invasive Aspergillosis and the impact of azole-resistance. Curr. Fungal Infect. Rep. https://doi.org/10.1007/s12281-023-00459-z (2023).
Perfect, J. R. et al. Editorial: Antifungal pipeline: build it strong; build it better! Front. Cell. Infect. Microbiol. 12, 881272 (2022).
pubmed: 35372097
pmcid: 8965832
doi: 10.3389/fcimb.2022.881272
Gow, N. A. R. et al. The importance of antimicrobial resistance in medical mycology. Nat. Commun. 13, 5352 (2022).
pubmed: 36097014
pmcid: 9466305
doi: 10.1038/s41467-022-32249-5
Lewis, R. E. Current concepts in antifungal pharmacology. Mayo Clin. Proc. 86, 805–817 (2011).
pubmed: 21803962
pmcid: 3146381
doi: 10.4065/mcp.2011.0247
McCarthy, M. W., Kontoyiannis, D. P., Cornely, O. A., Perfect, J. R. & Walsh, T. J. Novel agents and drug targets to meet the challenges of resistant fungi. J. Infect. Dis. 216, S474–s483 (2017).
pubmed: 28911042
doi: 10.1093/infdis/jix130
Fisher, M. C., Hawkins, N. J., Sanglard, D. & Gurr, S. J. Worldwide emergence of resistance to antifungal drugs challenges human health and food security. Science 360, 739–742 (2018).
pubmed: 29773744
doi: 10.1126/science.aap7999
Leonardi, R., Zhang, Y. M., Rock, C. O. & Jackowski, S. Coenzyme A: back in action. Prog. Lipid Res. 44, 125–153 (2005).
pubmed: 15893380
doi: 10.1016/j.plipres.2005.04.001
Bopp, S. et al. Potent acyl-CoA synthetase 10 inhibitors kill Plasmodium falciparum by disrupting triglyceride formation. Nat. Commun. 14, 1455 (2023).
pubmed: 36927839
pmcid: 10020447
doi: 10.1038/s41467-023-36921-2
Spry, C., Kirk, K. & Saliba, K. J. Coenzyme A biosynthesis: an antimicrobial drug target. FEMS Microbiol. Rev. 32, 56–106 (2008).
pubmed: 18173393
doi: 10.1111/j.1574-6976.2007.00093.x
Munshi, M. I., Yao, S. J. & Ben Mamoun, C. Redesigning therapies for pantothenate kinase-associated neurodegeneration. J. Biol. Chem. 298, 101577 (2022).
pubmed: 35041826
pmcid: 8861153
doi: 10.1016/j.jbc.2022.101577
Chiu, J. E. et al. The yeast pantothenate kinase Cab1 is a master regulator of sterol metabolism and of susceptibility to ergosterol biosynthesis inhibitors. J. Biol. Chem. 294, 14757–14767 (2019).
pubmed: 31409644
pmcid: 6779428
doi: 10.1074/jbc.RA119.009791
Olzhausen, J., Schubbe, S. & Schuller, H. J. Genetic analysis of coenzyme A biosynthesis in the yeast Saccharomyces cerevisiae: identification of a conditional mutation in the pantothenate kinase gene CAB1. Curr. Genet. 55, 163–173 (2009).
pubmed: 19266201
doi: 10.1007/s00294-009-0234-1
Ceccatelli Berti, C. et al. Evidence for a conserved function of eukaryotic pantothenate kinases in the regulation of mitochondrial homeostasis and oxidative stress. Int. J. Mol. Sci. 24. https://doi.org/10.3390/ijms24010435 (2022).
Ceccatelli Berti, C., Gilea, A. I., De Gregorio, M. A. & Goffrini, P. Exploring yeast as a study model of pantothenate kinase-associated neurodegeneration and for the identification of therapeutic compounds. Int. J. Mol. Sci. 22. https://doi.org/10.3390/ijms22010293 (2020).
Gihaz, S. et al. High-resolution crystal structure and chemical screening reveal pantothenate kinase as a new target for antifungal development. Structure 30, 1494–1507 e1496 (2022).
pubmed: 36167065
pmcid: 10042587
doi: 10.1016/j.str.2022.09.001
Sharma, L. K. et al. A therapeutic approach to pantothenate kinase-associated neurodegeneration. Nat. Commun. 9, 4399 (2018).
pubmed: 30352999
pmcid: 6199309
doi: 10.1038/s41467-018-06703-2
Schweizer, E. & Bolling, H. A Saccharomyces cerevisiae mutant defective in saturated fatty acid biosynthesis. Proc. Natl Acad. Sci. USA 67, 660–666 (1970).
pubmed: 4943177
pmcid: 283256
doi: 10.1073/pnas.67.2.660
Li, S. C. & Kane, P. M. The yeast lysosome-like vacuole: endpoint and crossroads. Biochim Biophys. Acta 1793, 650–663 (2009).
pubmed: 18786576
doi: 10.1016/j.bbamcr.2008.08.003
Raymond, C. K., Howald-Stevenson, I., Vater, C. A. & Stevens, T. H. Morphological classification of the yeast vacuolar protein sorting mutants: evidence for a prevacuolar compartment in class E vps mutants. Mol. Biol. Cell 3, 1389–1402 (1992).
pubmed: 1493335
pmcid: 275707
doi: 10.1091/mbc.3.12.1389
Hughes, A. L. & Gottschling, D. E. An early age increase in vacuolar pH limits mitochondrial function and lifespan in yeast. Nature 492, 261–265 (2012).
pubmed: 23172144
pmcid: 3521838
doi: 10.1038/nature11654
Hughes, C. E. et al. Cysteine toxicity drives age-related mitochondrial decline by altering iron homeostasis. Cell 180, 296–310 e218 (2020).
pubmed: 31978346
pmcid: 7164368
doi: 10.1016/j.cell.2019.12.035
Chouchani, E. T. et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 515, 431–435 (2014).
pubmed: 25383517
pmcid: 4255242
doi: 10.1038/nature13909
Mailloux, R. J. An Update on mitochondrial reactive oxygen species production. Antioxidants 9 https://doi.org/10.3390/antiox9060472 (2020).
Koselny, K. et al. The celecoxib derivative AR-12 has broad-spectrum antifungal activity in vitro and improves the activity of fluconazole in a murine model of cryptococcosis. Antimicrob. Agents Chemother. 60, 7115–7127 (2016).
pubmed: 27645246
pmcid: 5118990
doi: 10.1128/AAC.01061-16
Koselny, K. et al. Antitumor/antifungal celecoxib derivative AR-12 is a non-nucleoside inhibitor of the ANL-family adenylating enzyme acetyl CoA synthetase. ACS Infect. Dis. 2, 268–280 (2016).
pubmed: 27088128
pmcid: 4828684
doi: 10.1021/acsinfecdis.5b00134
Bowman, E. J. & Bowman, B. J. Cellular role of the V-ATPase in Neurospora crassa: analysis of mutants resistant to concanamycin or lacking the catalytic subunit A. J. Exp. Biol. 203, 97–106 (2000).
pubmed: 10600678
doi: 10.1242/jeb.203.1.97
Martinez-Munoz, G. A. & Kane, P. Vacuolar and plasma membrane proton pumps collaborate to achieve cytosolic pH homeostasis in yeast. J. Biol. Chem. 283, 20309–20319 (2008).
pubmed: 18502746
pmcid: 2459297
doi: 10.1074/jbc.M710470200
Berg, P. Acyl adenylates; an enzymatic mechanism of acetate activation. J. Biol. Chem. 222, 991–1013 (1956).
pubmed: 13367067
doi: 10.1016/S0021-9258(20)89957-8
Jogl, G. & Tong, L. Crystal structure of yeast acetyl-coenzyme A synthetase in complex with AMP. Biochemistry 43, 1425–1431 (2004).
pubmed: 14769018
doi: 10.1021/bi035911a
Jezewski, A. J. et al. Structural characterization of the reaction and substrate specificity mechanisms of pathogenic fungal acetyl-CoA synthetases. ACS Chem. Biol. 16, 1587–1599 (2021).
pubmed: 34369755
pmcid: 8383264
doi: 10.1021/acschembio.1c00484
de Jong-Gubbels, P., van den Berg, M. A., Steensma, H. Y., van Dijken, J. P. & Pronk, J. T. The Saccharomyces cerevisiae acetyl-coenzyme A synthetase encoded by the ACS1 gene, but not the ACS2-encoded enzyme, is subject to glucose catabolite inactivation. FEMS Microbiol. Lett. 153, 75–81 (1997).
pubmed: 9252575
doi: 10.1111/j.1574-6968.1997.tb10466.x
van den Berg, M. A. et al. The two acetyl-coenzyme A synthetases of Saccharomyces cerevisiae differ with respect to kinetic properties and transcriptional regulation. J. Biol. Chem. 271, 28953–28959 (1996).
pubmed: 8910545
doi: 10.1074/jbc.271.46.28953
Costanzo, M. et al. The genetic landscape of a cell. Science 327, 425–431 (2010).
pubmed: 20093466
pmcid: 5600254
doi: 10.1126/science.1180823
Costanzo, M. et al. A global genetic interaction network maps a wiring diagram of cellular function. Science 353. https://doi.org/10.1126/science.aaf1420 (2016).
Szappanos, B. et al. An integrated approach to characterize genetic interaction networks in yeast metabolism. Nat. Genet. 43, 656–662 (2011).
pubmed: 21623372
pmcid: 3125439
doi: 10.1038/ng.846
Arthington, B. A. et al. Cloning, disruption and sequence of the gene encoding yeast C-5 sterol desaturase. Gene 102, 39–44 (1991).
pubmed: 1864507
doi: 10.1016/0378-1119(91)90535-J
Parks, L. W., Smith, S. J. & Crowley, J. H. Biochemical and physiological effects of sterol alterations in yeast-a review. Lipids 30, 227–230 (1995).
pubmed: 7791530
doi: 10.1007/BF02537825
Zhang, Y. Q. et al. Requirement for ergosterol in V-ATPase function underlies antifungal activity of azole drugs. PLoS Pathog. 6, e1000939 (2010).
pubmed: 20532216
pmcid: 2880581
doi: 10.1371/journal.ppat.1000939
Bonangelino, C. J., Catlett, N. L. & Weisman, L. S. Vac7p, a novel vacuolar protein, is required for normal vacuole inheritance and morphology. Mol. Cell Biol. 17, 6847–6858 (1997).
pubmed: 9372916
pmcid: 232541
doi: 10.1128/MCB.17.12.6847
Dove, S. K. et al. Svp1p defines a family of phosphatidylinositol 3,5-bisphosphate effectors. EMBO J. 23, 1922–1933 (2004).
pubmed: 15103325
pmcid: 404323
doi: 10.1038/sj.emboj.7600203
Gary, J. D., Wurmser, A. E., Bonangelino, C. J., Weisman, L. S. & Emr, S. D. Fab1p is essential for PtdIns(3)P 5-kinase activity and the maintenance of vacuolar size and membrane homeostasis. J. Cell Biol. 143, 65–79 (1998).
pubmed: 9763421
pmcid: 2132800
doi: 10.1083/jcb.143.1.65
Nakatogawa, H., Suzuki, K., Kamada, Y. & Ohsumi, Y. Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat. Rev. Mol. Cell Biol. 10, 458–467 (2009).
pubmed: 19491929
doi: 10.1038/nrm2708
Kamada, Y., Sekito, T. & Ohsumi, Y. Autophagy in yeast: a TOR-mediated response to nutrient starvation. Curr. Top. Microbiol. Immunol. 279, 73–84 (2004).
pubmed: 14560952
Kraft, C. & Reggiori, F. Phagophore closure, autophagosome maturation and autophagosome fusion during macroautophagy in the yeast Saccharomyces cerevisiae. FEBS Lett. 598, 73–83 (2024).
pubmed: 37585559
doi: 10.1002/1873-3468.14720
BridgeBio, BridgeBio Pharma presents positive phase 1 data in healthy volunteers, advancing development of BBP-671 for pantothenate kinase-associated neurodegeneration (PKAN) and organic acidemias (2022).
BridgeBio, BridgeBio pharma announces dosing of first patient in phase 1 trial of BBP-671, a potential best-in-class treatment for propionic acidemia (PA) and methylmalonic acidemia (MMA) (2022).
Neubauer, S. et al. U13C cell extract of Pichia pastoris—a powerful tool for evaluation of sample preparation in metabolomics. J. Sep. Sci. 35, 3091–3105 (2012).
pubmed: 23086617
doi: 10.1002/jssc.201200447
Zhang, Y., Park, C., Bennett, C., Thornton, M. & Kim, D. Rapid and accurate alignment of nucleotide conversion sequencing reads with HISAT-3N. Genome Res. 31, 1290–1295 (2021).
pubmed: 34103331
pmcid: 8256862
doi: 10.1101/gr.275193.120
Fuller, K. K., Chen, S., Loros, J. J. & Dunlap, J. C. Development of the CRISPR/Cas9 system for targeted gene disruption in Aspergillus fumigatus. Eukaryot. Cell 14, 1073–1080 (2015).
pubmed: 26318395
pmcid: 4621320
doi: 10.1128/EC.00107-15
Mnaimneh, S. et al. Exploration of essential gene functions via titratable promoter alleles. Cell 118, 31–44 (2004).
pubmed: 15242642
doi: 10.1016/j.cell.2004.06.013
Gillum, A. M., Tsay, E. Y. & Kirsch, D. R. Isolation of the Candida albicans gene for orotidine-5’-phosphate decarboxylase by complementation of S. cerevisiae ura3 and E. coli pyrF mutations. Mol. Gen. Genet 198, 179–182 (1984).
pubmed: 6394964
doi: 10.1007/BF00328721
Fuller, K. K., Ringelberg, C. S., Loros, J. J. & Dunlap, J. C. The fungal pathogen Aspergillus fumigatus regulates growth, metabolism, and stress resistance in response to light. MBio 4. https://doi.org/10.1128/mBio.00142-13 (2013).